Food allergy includes both IgE-mediated disorders such as food-induced anaphylaxis and non-IgE- mediated disease such as food protein induced enterocolitis syndrome (FPIES). There are no currently recommended treatments beyond strict allergen avoidance. A feature shared by IgE-mediated and cell- mediated allergy is the presence of food allergen-specific Th2 cells producing IL-4, IL-13 and TNF1. Although our current understanding of various food allergic disorders places the Th2 cell in a central pathogenic role, there is a paucity of information about mechanisms of induction as well as effector mechanisms. The long-term goal is to understand how the T cell response to food allergens can be manipulated for therapeutic purposes. The objective of this proposal is to identify the pathogenic mechanisms of allergen-specific T cells in the gastrointestinal (GI) tract with emphasis on non-IgE- mediated FA. The hypothesis is that inflammatory T cells producing Th2 or other pathogenic cytokines accumulate in the gut mucosa and upon re-exposure to the allergen can directly induce GI dysfunction by acting on epithelial cells, smooth muscle, and sensory nerves. The rationale for the proposed research is that by understanding the phenotype and function of allergen-specific Th2 lymphocytes in the gastrointestinal tract, innovative targets will be identified for treatment of food allergy. To address this objective, the phenotype of allergen-specific T cells in human and experimental IgE-mediated and non-IgE- mediated food allergy will be determined. Next, the direct effect of allergen-induced Th2 cell activation on epithelial permeability, secretion, and intestinal motility will be quantified using in vivo, ex vivo and in vitro methodologies with murine and human specimens. Finally, the impact of allergen-specific Th2 cells on extrinsic sensory innervations of the gastrointestinal mucosa will be identified, and the role of sensory nerves in gastrointestinal manifestations of food allergy will be tested. The contribution of this research is significant because it will identify mechanisms involved in T cell-mediated gastrointestinal dysfunction, and thereby identifies new targets for therapeutic intervention. This research focuses on a shared feature of all food allergic disorders, the food allergen-specific Th2 lymphocyte, and therefore we anticipate that this research will be relevant to a broad spectrum of food allergic disorders. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the studied pathways are likely to provide new therapeutic targets for suppression of the mucosal T cell response. This research has relevance not only to food allergic disorders, but also to immune-mediated gastrointestinal disorders such as inflammatory bowel disease and to mucosal vaccination.